Mesenchymal and adrenergic cell lineage states in neuroblastoma possess distinct immunogenic phenotypes

Satyaki Sengupta, Sanjukta Das, Angela C. Crespo, Annelisa M. Cornel, Anand G. Patel, Navin R. Mahadevan, Marco Campisi, Alaa K. Ali, Bandana Sharma, Jared H. Rowe, Hao Huang, David N. Debruyne, Esther D. Cerda, Malgorzata Krajewska, Ruben Dries, Minyue Chen, Shupei Zhang, Luigi Soriano, Malkiel A. Cohen, Rogier VersteegRudolf Jaenisch, Stefani Spranger, Rizwan Romee, Brian C. Miller, David A. Barbie, Stefan Nierkens, Michael A. Dyer, Judy Lieberman, Rani E. George

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)


Apart from the anti-GD2 antibody, immunotherapy for neuroblastoma has had limited success due to immune evasion mechanisms, coupled with an incomplete understanding of predictors of response. Here, from bulk and single-cell transcriptomic analyses, we identify a subset of neuroblastomas enriched for transcripts associated with immune activation and inhibition and show that these are predominantly characterized by gene expression signatures of the mesenchymal lineage state. By contrast, tumors expressing adrenergic lineage signatures are less immunogenic. The inherent presence or induction of the mesenchymal state through transcriptional reprogramming or therapy resistance is accompanied by innate and adaptive immune gene activation through epigenetic remodeling. Mesenchymal lineage cells promote T cell infiltration by secreting inflammatory cytokines, are efficiently targeted by cytotoxic T and natural killer cells and respond to immune checkpoint blockade. Together, we demonstrate that distinct immunogenic phenotypes define the divergent lineage states of neuroblastoma and highlight the immunogenic potential of the mesenchymal lineage.

Original languageEnglish
Pages (from-to)1228-1246
Number of pages19
JournalNature Cancer
Issue number10
Publication statusPublished - Oct 2022
Externally publishedYes


  • Humans
  • Cell Lineage/genetics
  • Adrenergic Agents
  • Immune Checkpoint Inhibitors
  • Neuroblastoma/genetics
  • Cytokines/genetics
  • Phenotype


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